The importance of genotypic differences in the susceptibility to alcoholism in man, and their influence on ethanol sensitivity, tolerance, and withdrawal severity in animals, is achieving ever greated recognition. While we know that susceptibility to almost all aspects of alcohol's effects in animals is to some degree inherited, we have little idea yet what specifically is inherited. The proposed research will provide an animal genetic model that will allow us to unravel some of the genetic relationships among different aspects of ethanol responsiveness. The proposed project will develop lines of mice that differ genetically in their sensitivity to ethanol's effect to lower body temperature in a cool ambient environment. Using within-family selective breeding, two Hypothermia Prone (HTP) and two Hypothermia Resistant (HTR) lines will be developed. Two concurrent controls (HTC) will be established and maintained. The existence of replicate lines will allow clear differentiation of correlated responses to selection from those arising between the a given pair of HTP and HTR lines by chance. Methods will be adopted to insure that the lines differ in hypothermic sensitivity to the same brain level of ethanol. The major long-term goal of the proposed selective breeding study is to shed light on an ubiquitous, easily assessed response to ethanol (hypothermia) that is useful as an index of sensitivity, tolerance and withdrawal from physical dependence on ethanol. The lines of animals to be selected should have interest for investigators interested in the pharmacology of thermoregulation as well as alcohol dependence. Previous research has identified thermoregulatory responses to ethanol as key responses that may mediate other effects of the drug, such as central nervous system depression. The successful selection of the proposed lines could provide a much-needed genetic marker for predicting the susceptibility to develop ethanol physical dependence.